An implant for subcutaneous or intradermal

 

(57) Abstract:

The invention relates to medicine, namely to a restorative or cosmetic surgery and aesthetic dermatology. An implant for subcutaneous or intradermal man in the form of injections consists of biologically decomposable microspheres or microparticles in suspension in a gel, where the said microspheres or microparticles are composed of at least one polymer selected from polymers of lactic acid, polymers of glycolic acid and copolymers of lactic acid and glycolic acid. The implant can be obtained in the form of a lyophilisate, capable of adding water for injection to injecting the implant. The implant has resorbable within 1-3 years, does not cause allergic reactions. 2 C. and 8 C.p. f-crystals.

The invention relates to an implant for subcutaneous or intradermal, intended for use in reconstructive, or plastic surgery man and aesthetic dermatology, to fill wrinkles, wrinkles, skin depressions, acne scars and other scars, as well as in odontostomatologia to fill gums.

Until today, headed the remainder.

Easy to use is silicone gel or silicone oil). However, it was found that after injection of observed migration of the silicone droplets in the tissue beneath the point of injection, by simple gravity. Silicone is often the cause of chronic inflammation, the formation of granulomas and even late allergic reactions. The silicone is not subject to biological degradation, and it is often found in the liver.

Teflon paste is a suspension of particles of polytetrafluoroethylene (diameter of 10-100 μm) in glycerol. In many cases this product provokes serious, severe and chronic infection, and for most patients want to remove it after a few months of skin and subcutaneous tissue. It has also been shown that small particles of polytetrafluoroethylene can be detected in the liver.

In the last ten years of very extensive use of the collagen suspension. However, the results are quite satisfactory in that the collagen is absorbed in 1-3 months. Also approximately 2% of patients had allergic reactions. Finally, it should be noted that the collagen is bovine collagen.

C showed the failure of reimplantation of fat cells, which are absorbed and disappear within a few weeks.

Another system is to add the plasma of the patient in the collagen of bovine gelatin and porcine origin. The results are even more unsatisfactory, and the product is of animal origin.

Gialuronatnye gels are a good alternative because of their biocompatibility and lack of toxicity. In addition, they are widely used in eye surgery. However, their rapid biological resorbable (maximum 2 months) makes them ineffective for use in plastic surgery.

Bioplastics are polymerized silicone particles (diameter 70-140 µm) dispersed in polyvinylpyrrolidone. The product must be extracted, whereas chronic inflammation and rejection that it provokes.

There are beads of polymethylmethacrylate (PMMA) with a diameter of 20-40 μm in the form of a suspension or solution of gelatin, or in a solution of collagen. PMMA is not subject to biological degradation, but lack the time necessary to get to know what makes this implant after 5 or 6 years. In addition, the vector is a solution collagenase eliminating the disadvantages of the known products.

According to the invention using microspheres or microparticles formed neutral polymer, chosen because of its safety and is already widely used in the pharmaceutical industry, where it is administered either orally or parenterally.

The implant according to the invention combines the ease of use without prior manipulation, the possibility of introducing product a syringe, resorbable, during the controlled time of the polymer as a vector of gel, no allergiesthe product, which makes it unnecessary preliminary test.

Microspheres or microparticles should have controlled biological resorbable providing a resorbable time of 1 to 3 years. This means that the polymer after injection in situ degraded to low molecular weight compounds, which are removed from the body through natural processes. In any case nerenormiruemye implant is not desirable. It is always about the foreign body introduced into the living tissue.

Microspheres or microparticles are suspended in the gel. They must have a diameter greater than 5 microns, and preferably more than 20 μm, that they are not absorbed macrophages. They should Yotzei using a thin needle, and, on the other hand, do not create granular accumulations under the finger.

Essentially two classes of polymers meet the above definition: polycaprolactones (especially poly--caprolactone), as well as polylactide polymers of lactic acid or PLA), polyglycolides (polymer of glycolic acid or PGA) and their copolymers (copolymers of lactic acid and glycolic acid or PLAGA).

Whereas numerous studies already carried out and widely known products, in terms of the manufacture of the microspheres and resorbable, is preferable to use a mixture of polylactic acid (PLA) with a copolymer of lactic acid and glycolic acid (PLAGA). The proportions of each of these two acids can determine the residual effect of the product.

Numerous experiments also lead to the preference of the polymer is a polymer of L-lactic acid (crystalline) polymer of D-lactic acid (amorphous) or the polymer mixture of these two acids. Its molecular weight is calculated by viscosity, is preferably from 70,000 to the 175,000 daltons, and preferably from to 120000 170000 Dalton, internal viscosity is 3-4 DL/g, and provides 178,0-190,1oC, the heat of melting is 85,0 to 90.0 j/g, the amount of residual solvent of less than 0.01%, and the proportion of the residual monomer (lactic acid) less than 0.1%. This product is manufactured by a company PURAC WONEM in Gorinchem (Netherlands).

Biologically resorbed synthetic polymers for about fifteen years examined under the leadership of Michel VERT, Director of scientific-research works in C. N. R. S. the First clinical application of PLA started in 1981 for a variety of indications in facial trauma. Polymers of lactic acid is now used systematically in the framework of biologically resorbed surgical implants. Application in medicine PLA today is diverse and extensive (bone surgery, maxillofacial surgery, pharmacological formulations of controlled release: implants, microspheres, nanospheres, vaccines).

The destruction of polymers of lactic acid and/or glycolic acid in a biological environment is solely on the chemical mechanism of nonspecific hydrolysis. The products of this hydrolysis are then transformed in the process of metabolism, then removed from the human body. Chemical hydrolysis of the polymer is complete, the way, the time can be adjusted by resorbable impact on the composition of the mixture and/or the molecular weight of the polymer or polymers. Biological compatibility of polymers PLA and PLAGA makes them an excellent basis for cell growth and tissue regeneration.

Microspheres or microparticles included in the gel. This gel is used as a vector to maintain the microspheres or microparticles in the form of a homogeneous suspension is resorbed in about 2 months, which corresponds to the time required to create fibrosis around the microspheres or microparticles. It mainly consists of water used to prepare drugs for injection and gel-forming component allowed for the injection of: cellulose derivatives, in particular carboxymethylcellulose (CMC), at a concentration of 0.1 to 7.5 wt. percent, and preferably 0.1 to 5.0 wt.%. You can also resort to the use of hydroxypropylmethylcellulose (receiver array), which is usually used for intraocular injection operations for cataract. You can also use synthetic hyaluronic acid used for intraocular injection and subcutaneous injection. You can also use the esters of lactic acid, esters of Caproic acid, etc.

On Resto-active substances, selected for its safety and its permitted uses subcutaneously or intradermally. Using polyoxyethylene sorbitan monooleate (being sold under the name tween 80) or pornowww acid.

The product can be pre-filled syringe of sterile, ready-to-use and equipped with a needle, or in vials with sterile suspension. It can also be placed in the vial containing the lyophilized attached vial with sterile water (water to prepare drugs for injection), or in pre-filled syringe with two branches, of which one contains the freeze-dried microspheres or microparticles, and the other contains water to prepare drugs for injection.

The implant does not require testing for allergic reactions. It contains no animal products.

The Protocol for production of the implant in the case of ready-to-use suspension of microspheres is described below.

A. Obtaining microspheres of polylactic acid. Use the classic way or solvent evaporation method, called controlled precipitation, or any other way to get microsphere suspension. This viscosity change depending on the particle size of the microspheres and the quantity dispersed in the gel microspheres. This amount is 50-300 g/l, and preferably 60-200 g/L.

Century Distribution of gel in syringes or vials in a controlled atmosphere (class 104).

G. Sterilization of vials or syringes, or use of the process, making the final product suitable for administration by injection subcutaneously.

The following describes the Protocol for production of lyophilized microparticles PLA, when it comes to polymer L, D polymer or mixtures thereof:

A. Croissanterie PLA in the atmosphere of nitrogen gas passed through a filter with a pore size of 0.22 μm, at a temperature below -80oWith on the sieve to sift the size of the holes in the light of 100 μm.

B. Screening of microparticles through a stainless steel sieve with the hole size in the light of 100 microns.

C. Preparation of the environment for lyophilization, comprising dissolving under stirring CMC (gel component), pyrogen-free mannitol (createsite agent) and Polysorbate (surfactant) in water to prepare drugs for injection, filtering the resulting solution through a filter with pore size 0,22 20 minutes at a temperature of 121,5oC.

, The Distribution of microparticles of 100 mg per vial with a nominal capacity of 4 ml.

D. the Distribution medium for lyophilization to 1,050,05 g vials containing microparticles of polylactic acid.

That is, the Dispersion of the microparticles in the environment for lyophilization using the system for dispersing by ultrasound, in order to obtain a homogeneous suspension.

J. Preliminary plugging bottles with corks with stanchions (specific for lyophilization), rapid freezing to temperatures below -70oC, storage of frozen vials at temperatures below -40oC and, finally, lyophilization and automatic plugging bottles.

H. Sealing caps and checked for clearance bottles before sterilization by radiation.

Of course, you can combine the above methods work, for example, to obtain a ready to use suspension of microparticles or freeze-dried microspheres and microparticles or microspheres formed by any of the above polymers and mixtures thereof.

Example 1

2 g of PLA was dissolved in 20 ml of organic solvent (ethyl acetate). This solution was dispersed in 100 ml of water containing the rhenium solvent and the formation of microspheres with an average diameter of 40 microns. The microspheres formed recovered by sedimentation, filtration and drying. They are then in a gel consisting of water and CMC (0.5%). After moderate mixing distribution is carried out.

Example 2

2 g of PLA was dissolved in 20 ml of organic solvent (dihlormetilen). This solution was dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring Vortex continue until evaporation of the solvent and the formation of microspheres with an average diameter of 80 μm. The microspheres formed recovered by sedimentation, filtration and drying. They are then in a gel consisting of water and CMC (0.5%). After moderate mixing distribution is carried out.

Example 3

2 g of PLA was dissolved in 20 ml of organic solvent (chloroform). This solution was dispersed in 100 ml of water containing 5 g of polyoxyethylene sorbitan monooleate. Moderate stirring Vortex continue until evaporation of the solvent and the formation of microspheres with an average diameter of 50 μm. The microspheres formed recovered by sedimentation, filtration and drying. They are then in a gel consisting of water and a receiver array (1 wt.%). After amarinalameda lactic acid to a final particle size of 20 to 100 microns, with a median of 40 μm. These microparticles are distributed to 100 mg per vial.

Prepare a 6.5 kg environment for lyophilization by dissolving 97.5 g of sodium CMC, 276,25 g apyrogenic mannitol and 6.5 g of Polysorbate 80 in sufficient to 6.5 l of water to prepare drugs for injection. The medium was dispensed into 1 g per vial.

With the products of examples 1-4 conducted experiments on animals (hairless mice and new Zealand rabbits). The results are the same, and for the first two months, starting from the eighth day after the injection, see the appearance of giant cells surrounding the grid crystals lactic acid polymer, then their transformation through the creation of fibrosis, which restores the subcutaneous tissue.

1. Injectable implant for subcutaneous or intradermal man in the form of injections, consisting of biologically decomposable microspheres or microparticles in suspension in a gel, despite the fact that these microspheres or microparticles are composed of at least one polymer selected from polymers of lactic acid, polymers of glycolic acid and copolymers of lactic acid and glycolic acid.

2. The implant according to p. 1, characterized in that the content of microfi the decomposing those what microspheres or microparticles have an average diameter of 5-150 μm, preferably 20-40 μm.

4. The implant according to any of paragraphs.1-3, characterized in that the microspheres or microparticles are biodegradable over a period of 1-3 years.

5. The implant according to any of paragraphs.1-4, characterized in that said polymer is polylactic acid selected from poly-L-lactic acid, poly-D-lactic acid, and mixtures thereof.

6. The implant according to p. 5, wherein the polylactic acid is characterized by a molecular weight 70000-175000 daltons, preferably 120000-170000 Dalton, internal viscosity 3-4 DL/g, preferably at 3.35-3,65 DL/g, the percentage residual monomer content less than 0.1%, and the percentage content of residual solvents is less than 0.01%.

7. The implant according to any of paragraphs.1-6, characterized in that the gel includes as a gelling component mainly carboxymethylcellulose (CMC) or hypromellose (receiver array) at a concentration of 0.1 to 7.5 wt.%, preferably 0.1 to 5.0 wt.%.

8. The implant according to any of paragraphs.1-7 used in reconstructive or cosmetic surgery and aesthetic dermatology to fill wrinkles, wrinkles, skin cracks, scars from acne and Dali injectable implant according to any of paragraphs.1-7 and is able to injecting the implant for subcutaneous or intradermal by adding water for injection.

10. The lyophilisate according to p. 9 used in reconstructive or plastic surgery man and aesthetic dermatology to fill wrinkles, wrinkles, skin cracks, scars from acne and other scars, as well as in dentistry for filling gums.

 

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